Mechanism of induction of prostaglandin E2 production by endothelin 1 in cultured rat mesangial cells.

The phospholipase A2 inhibitors mepacrine, ONO-RS-082, and AACOCF3 completely inhibited prostaglandin E2 production induced by endothelin 1 in cultured rat mesangial cells, suggesting that phospholipase A2 is a critical enzyme in this process. TMB-8, an inhibitor of calcium mobilization from intracellular stores, abolished its production, while neither nicardipine nor chelation of extracellular calcium by EGTA did. The protein kinase C inhibitors, H-7 and staurosporine, and downregulation of protein kinase C could not inhibit prostaglandin E2 production, while W-7, a calmodulin inhibitor, abolished it. Pertussis toxin never influenced its production. Thus, endothelin 1 evokes prostaglandin E2 production in mesangial cells mainly through the activation of phospholipase A2, dependent on intracellular calcium and calmodulin and independent of extracellular calcium, protein kinase C, and pertussis toxin sensitive guanosine 5'-triphosphate binding proteins.